THE MOLECULAR CANCER SUBTYPES VERSUS THE INDUSTRY ARSENAL. WHICH ONE DRIVES GASTRIC CANCER TREATMENT?

ABSTRACT Molecular medicine opened new horizons in understanding disease mechanisms and discovering target interventions. The wider availability of DNA and RNA sequencing, immunohistochemical analysis, proteomics, and other molecular tests changed how physicians manage diseases. The gastric cancer molecular classification proposed by The Cancer Genome Atlas Program divides gastric adenocarcinomas into four subtypes. However, the available targets and/or immunotherapies approved for clinical use seem to be dissociated from these molecular subtypes. Until a more reliable interpretation of the stupendous amount of data provided by the molecular classifications is presented, the clinical guidelines will rely on available actionable targets and approved therapies to guide clinicians in conducting cancer management in the era of molecular therapies.


A QUEDA PRESSÃO PORTAL APÓS DESVASCULARIZAÇÃO ESOFAGOGÁSTRICA E ESPLENECTOMIA INFLUENCIA A VARIAÇÃO DO CALIBRE VARIZES E AS DE RESSANGRAMENTO ESQUISTOSSOMOSE NO SEGUIMENTO LONGO PRAZO?
Does the drop in portal pressure after esophagogastric devascularization and splenectomy variation of variceal calibers and the rebleeding rates in schistosomiasis in late follow-up?
Walter de Biase SILVA-NETO 1 , Claudemiro QUIRESE 1 , Eduardo Guimarães Horneaux de MOURA 2 , Fabricio Ferreira COELHO 3 , Paulo HERMAN 3 ABSTRACT -Background: The treatment of choice for patients with schistosomiasis with previous episode of varices is bleeding esophagogastric devascularization and splenectomy (EGDS) in association with postoperative endoscopic therapy.However, studies have shown varices recurrence especially after long-term follow-up.Aim: To assess the impact on behavior of esophageal varices and bleeding recurrence after post-operative endoscopic treatment of patients submitted to EGDS.Methods: Thirty-six patients submitted to EGDS portal pressure drop, more or less than 30%, and compared the behavior of esophageal varices and the rate of bleeding recurrence.Results late post-operative varices caliber when compared the pre-operative data was observed despite an increase in diameter during follow-up that was controlled by endoscopic therapy.

Conclusion variceal calibers when comparing pre-operative and early or late post-operative
The comparison between the portal pressure drop and the rebleeding rates was also not The dissociation between the molecular classification and indications for specific therapies does not diminish the importance of the molecular classifications.These classifications provide robust information for the development of new therapies and shed light on the understanding of each cancer molecular mechanism, allowing future interventions in treatment, diagnosis, and prevention strategies, the latter being the most effective future cancer control 8,9 .
Until a more reliable interpretation of the stupendous amount of data provided by the molecular classifications is presented, the clinical guidelines will rely on available actionable targets and approved therapies to guide clinicians in conducting cancer management in the era of molecular therapies.Currently, the available industry arsenal has greater weight than the molecular classifications themselves in the clinical treatment decision-making 2,3 .

INTRODUCTION
Molecular medicine opened new horizons in understanding disease mechanisms and discovering target interventions.The wide availability of DNA and RNA sequencing, immunohistochemical analysis, proteomics, and other molecular tests changed how physicians manage diseases.
This revolution reached almost every field of medicine but was especially incorporated into oncology.Cancers that were unresponsive to classical therapies are now treated with great success, as a consequence of both understanding their molecular mechanisms and the development of specific target therapies to hone in on them.
Academic research institutions and the pharmaceutical industry have triggered the discovery of many new sensitive targets, translating them into daily practice.
This development in molecular understanding gave rise to the precision medicine initiative, which emerged as a strategy to treat patients more efficiently, according to both the molecular features of the tumor and the peculiarities of the individual genetic background, including pharmacogenetic variants.
Diverse initiatives to classify cancers beyond the traditional morphological histological criteria, which incorporate the molecular patterns of the tumors and aim to guide their clinical management, have emerged and become extensively reported in medical journals 1,6 .
Nevertheless, in the real world, treatment decisions are mostly driven by available target therapies based on protocols of potential clinical response, instead of by molecular classifications 10 .
The Cancer Genome Atlas Program (TCGA) consortium provided molecular classifications of many cancer types, including gastric, colonic, and others.The scientific community expected to translate these classifications into clinical decisions, but this goal seems very far from the daily practice 5 .
The gastric cancer molecular classification proposed by the TCGA divides gastric adenocarcinomas into four subtypes.However, the available targets and/or immunotherapies approved for clinical use seem to be dissociated from these molecular subtypes 5 .
Anti-HER-2 therapies, although most commonly applied to the Chromosomal instability molecular subtype (CIN), are also indicated for tumors from the other subtypes, as long as they present high human epidermal growth factor receptor-type 2 (HER-2) expression.The same is true for Claudin 18-2.Target therapy will be available for every molecular subtype according to antibody reactivity to Claudin-2.Anti-PD-1 therapy is indicated for a specific molecular subtype, the Microsatellites Instability molecular subtype (MSI).But even for this indication, if a tumor from other molecular subtypes presents a high expression of PD-1 (combined positive score [CPS]>1), this therapy will be made available for clinical use.Moreover, Epstein-Barr virus (EBV) subtypes and cancers with a high tumor mutation burden also represent potential indications for such therapy 3,4 .
These "directed by available therapy" classifications are also present in the management of many other cancer types, such as lung, breast, and melanoma, among others.
The agnostic indication is the most extreme example of treatment guided by available actionable target therapies.Accordingly, if the target is presented, treatment will be indicated, regardless of the tumor type or site of origin, whether it is gastric, colonic, pulmonary, uterine, or other cancers; once the target is present, a drug will be indicated.Should this still be called "precision medicine"? 1,7.